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Overview

Uniprot IDQ9Y4H2
Protein NameInsulin receptor substrate 2
Gene NameIRS2
OrganismHomo sapiens

Kla Sites from experimental identification

Position Flanking peptide
355 AATPPAAKCSSCRVR

Function

Signaling adapter protein that participates in the signal transduction from two prominent receptor tyrosine kinases, insulin receptor/INSR and insulin-like growth factor I receptor/IGF1R (PubMed:25879670). Plays therefore an important role in development, growth, glucose homeostasis as well as lipid metabolism (PubMed:24616100). Upon phosphorylation by the insulin receptor, functions as a signaling scaffold that propagates insulin action through binding to SH2 domain-containing proteins including the p85 regulatory subunit of PI3K, NCK1, NCK2, GRB2 or SHP2 (PubMed:15316008, PubMed:19109239). Recruitment of GRB2 leads to the activation of the guanine nucleotide exchange factor SOS1 which in turn triggers the Ras/Raf/MEK/MAPK signaling cascade (By similarity). Activation of the PI3K/AKT pathway is responsible for most of insulin metabolic effects in the cell, and the Ras/Raf/MEK/MAPK is involved in the regulation of gene expression and in cooperation with the PI3K pathway regulates cell growth and differentiation. Acts a positive regulator of the Wnt/beta-catenin signaling pathway through suppression of DVL2 autophagy-mediated degradation leading to cell proliferation (PubMed:24616100). Plays a role in cell cycle progression by promoting a robust spindle assembly checkpoint (SAC) during M-phase (PubMed:32554797). In macrophages, IL4-induced tyrosine phosphorylation of IRS2 leads to the recruitment and activation of phosphoinositide 3-kinase (PI3K) (PubMed:19109239)

Protein Sequence

10 MASPPRHGPP 20 GPASGDGPNL 30 NNNNNNNNHS 40 VRKCGYLRKQ 50 KHGHKRFFVL 60 RGPGAGGDEA 70 TAGGGSAPQP 80 PRLEYYESEK 90 KWRSKAGAPK 100 RVIALDCCLN 110 INKRADAKHK 120 YLIALYTKDE 130 YFAVAAENEQ 140 EQEGWYRALT 150 DLVSEGRAAA 160 GDAPPAAAPA 170 ASCSASLPGA 180 LGGSAGAAGA 190 EDSYGLVAPA 200 TAAYREVWQV 210 NLKPKGLGQS 220 KNLTGVYRLC 230 LSARTIGFVK 240 LNCEQPSVTL 250 QLMNIRRCGH 260 SDSFFFIEVG 270 RSAVTGPGEL 280 WMQADDSVVA 290 QNIHETILEA 300 MKALKELFEF 310 RPRSKSQSSG 320 SSATHPISVP 330 GARRHHHLVN 340 LPPSQTGLVR 350 RSRTDSLAAT 360 PPAAKCSSCR 370 VRTASEGDGG 380 AAAGAAAAGA 390 RPVSVAGSPL 400 SPGPVRAPLS 410 RSHTLSGGCG 420 GRGSKVALLP 430 AGGALQHSRS 440 MSMPVAHSPP 450 AATSPGSLSS 460 SSGHGSGSYP 470 PPPGPHPPLP 480 HPLHHGPGQR 490 PSSGSASASG 500 SPSDPGFMSL 510 DEYGSSPGDL 520 RAFCSHRSNT 530 PESIAETPPA 540 RDGGGGGEFY 550 GYMTMDRPLS 560 HCGRSYRRVS 570 GDAAQDLDRG 580 LRKRTYSLTT 590 PARQRPVPQP 600 SSASLDEYTL 610 MRATFSGSAG 620 RLCPSCPASS 630 PKVAYHPYPE 640 DYGDIEIGSH 650 RSSSSNLGAD 660 DGYMPMTPGA 670 ALAGSGSGSC 680 RSDDYMPMSP 690 ASVSAPKQIL 700 QPRAAAAAAA 710 AVPSAGPAGP 720 APTSAAGRTF 730 PASGGGYKAS 740 SPAESSPEDS 750 GYMRMWCGSK 760 LSMEHADGKL 770 LPNGDYLNVS 780 PSDAVTTGTP 790 PDFFSAALHP 800 GGEPLRGVPG 810 CCYSSLPRSY 820 KAPYTCGGDS 830 DQYVLMSSPV 840 GRILEEERLE 850 PQATPGPSQA 860 ASAFGAGPTQ 870 PPHPVVPSPV 880 RPSGGRPEGF 890 LGQRGRAVRP 900 TRLSLEGLPS 910 LPSMHEYPLP 920 PEPKSPGEYI 930 NIDFGEPGAR 940 LSPPAPPLLA 950 SAASSSSLLS 960 ASSPASSLGS 970 GTPGTSSDSR 980 QRSPLSDYMN 990 LDFSSPKSPK 1000 PGAPSGHPVG 1010 SLDGLLSPEA 1020 SSPYPPLPPR 1030 PSASPSSSLQ 1040 PPPPPPAPGE 1050 LYRLPPASAV 1060 ATAQGPGAAS 1070 SLSSDTGDNG 1080 DYTEMAFGVA 1090 ATPPQPIAAP 1100 PKPEAARVAS 1110 PTSGVKRLSL 1120 MEQVSGVEAF 1130 LQASQPPDPH 1140 RGAKVIRADP 1150 QGGRRRHSSE 1160 TFSSTTTVTP 1170 VSPSFAHNPK 1180 RHNSASVENV 1190 SLRKSSEGGV 1200 GVGPGGGDEP 1210 PTSPRQLQPA 1220 PPLAPQGRPW 1230 TPGQPGGLVG 1240 CPGSGGSPMR 1250 RETSAGFQNG 1260 LNYIAIDVRE 1270 EPGLPPQPQP 1280 PPPPLPQPGD 1290 KSSWGRTRSL 1300 GGLISAVGVG 1310 STGGGCGGPG 1320 PGALPPANTY 1330 ASIDFLSHHL KEATIVKE

Gene Ontology

Classification GO ID Description
Cellular Component GO:0005737 cytoplasm
Cellular Component GO:0005829 cytosol
Cellular Component GO:0005886 plasma membrane
Molecular Function GO:0071889 14-3-3 protein binding
Molecular Function GO:0005158 insulin receptor binding
Molecular Function GO:0141038 phosphatidylinositol 3-kinase activator activity
Molecular Function GO:0043548 phosphatidylinositol 3-kinase binding
Molecular Function GO:0019904 protein domain specific binding
Molecular Function GO:0019903 protein phosphatase binding
Molecular Function GO:0035591 signaling adaptor activity
Molecular Function GO:0005068 transmembrane receptor protein tyrosine kinase adaptor activity
Biological Process GO:1990859 cellular response to endothelin
Biological Process GO:0071333 cellular response to glucose stimulus
Biological Process GO:0032869 cellular response to insulin stimulus
Biological Process GO:0006006 glucose metabolic process
Biological Process GO:0008286 insulin receptor signaling pathway
Biological Process GO:0048009 insulin-like growth factor receptor signaling pathway
Biological Process GO:0055088 lipid homeostasis
Biological Process GO:0002903 negative regulation of B cell apoptotic process
Biological Process GO:0010748 negative regulation of long-chain fatty acid import across plasma membrane
Biological Process GO:0030890 positive regulation of B cell proliferation
Biological Process GO:0008284 positive regulation of cell population proliferation
Biological Process GO:0046326 positive regulation of D-glucose import across plasma membrane
Biological Process GO:0032000 positive regulation of fatty acid beta-oxidation
Biological Process GO:0010907 positive regulation of glucose metabolic process
Biological Process GO:0045725 positive regulation of glycogen biosynthetic process
Biological Process GO:0032024 positive regulation of insulin secretion
Biological Process GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
Biological Process GO:0019216 regulation of lipid metabolic process
Biological Process GO:0009749 response to glucose
Biological Process GO:0007165 signal transduction

Reference

[1] Yang Z, Yan C, Ma J, Peng P, Ren X et al.. Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma.. Nat Metab 5(1):61-79. 2023 Jan. PMID: 36593272.